title: Pathogenic rare copy number variants in community-based schizophrenia suggest a potential role for clinical microarrays.
abstract: Individually rare, large copy number variants (CNVs) contribute to genetic vulnerability for schizophrenia. Unresolved questions remain, however, regarding the anticipated yield of clinical microarray testing in schizophrenia. Using high-resolution genome-wide microarrays and rigorous methods, we investigated rare CNVs in a prospectively recruited community-based cohort of 459 unrelated adults with schizophrenia and estimated the minimum prevalence of clinically significant CNVs that would be detectable on a clinical microarray. A blinded review by two independent clinical cytogenetic laboratory directors of all large (>500 kb) rare CNVs in cases and well-matched controls showed that those deemed to be clinically significant were highly enriched in schizophrenia (16.4-fold increase, P < 0.0001). In a single community catchment area, the prevalence of individuals with these CNVs was 8.1%. Rare 1.7 Mb CNVs at 2q13 were found to be significantly associated with schizophrenia for the first time, compared with the prevalence in 23 838 population-based controls (42.9-fold increase, P = 0.0002). Additional novel findings that will facilitate the future clinical interpretation of smaller CNVs in schizophrenia include: (i) a greater proportion of individuals with two or more rare exonic CNVs >10 kb in size (1.5-fold increase, P = 0.0109) in schizophrenia; (ii) the systematic discovery of new candidate genes for schizophrenia; and, (iii) functional gene enrichment mapping highlighting a differential impact in schizophrenia of rare exonic deletions involving diverse functions, including neurodevelopmental and synaptic processes (4.7-fold increase, P = 0.0060). These findings suggest consideration of a potential role for clinical microarray testing in schizophrenia, as is now the suggested standard of care for related developmental disorders like autism.
authors.affiliation: Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, ON, Canada M5S 2S1.
authors.forename: Gregory
authors.initials: G
authors.lastname: Costain
authors.forename: Anath C
authors.initials: AC
authors.lastname: Lionel
authors.forename: Daniele
authors.initials: D
authors.lastname: Merico
authors.forename: Pamela
authors.initials: P
authors.lastname: Forsythe
authors.forename: Kathryn
authors.initials: K
authors.lastname: Russell
authors.forename: Chelsea
authors.initials: C
authors.lastname: Lowther
authors.forename: Tracy
authors.initials: T
authors.lastname: Yuen
authors.forename: Janice
authors.initials: J
authors.lastname: Husted
authors.forename: Dimitri J
authors.initials: DJ
authors.lastname: Stavropoulos
authors.forename: Marsha
authors.initials: M
authors.lastname: Speevak
authors.forename: Eva W C
authors.initials: EW
authors.lastname: Chow
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.forename: Anne S
authors.initials: AS
authors.lastname: Bassett
mesh_terms: D000328:Adult; D002889:Chromosomes, Human, Pair 2; D056915:DNA Copy Number Variations; D005091:Exons; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D011446:Prospective Studies; D012559:Schizophrenia / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D017384:Sequence Deletion